Optically transparent hydrogels and processes for their production

ABSTRACT

The invention provides hydrogels for use in the production of biomedical devices. In particular, the invention provides hydrogels formed from siloxane prepolymers and a hydrophilic monomer, which hydrogels are optically transparent.

This application is a Reissue of U.S. appln. No. 09/163,693, now issuedas U.S. Pat. No. 6,031,059.

FIELD OF THE INVENTION

The invention relates to hydrogels for use in the production ofbiomedical devices. In particular, the invention provides hydrogelsformed from siloxane prepolymers and a hydrophilic monomer, whichhydrogels are optically transparent.

BACKGROUND OF THE INVENTION

The use of hydrogels for the manufacture of biomedical devices is known.Hydrogels that are copolymers of siloxane prepolymers and hydrophilicmonomers offer certain advantages in comparison with conventionalhydrogels. However, it is difficult to produce optically transparent,homogeneous hydrogels from these prepolymers and monomers making the useof the hydrogels limited.

Known methods for making homogeneous hydrogels from siloxane prepolymersinclude using diluents to compatabilize the siloxane with thehydrophilic monomer and using siloxanes into which hydrophilic groupsare incorporated. However, the use of diluents is disadvantageousbecause of their volatility and their use may result in polymers ofinferior quality. Incorporation of hydrophilic groups is disadvantageousin that it requires the use of complicated syntheses and the resultingpolymer may not be optically transparent. Therefore, a need exists for amethod of polymerizing siloxane prepolymers and hydrophilic monomersthat overcome these disadvantages.

DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

It is a discovery of the invention that homogeneous, opticallytransparent hydrogels can be formed from the polymerization of siloxaneprepolymers and/or monomers with a hydrophilic monomer withoutincorporation of hydrophilic groups into the siloxane and with areduction in the amount of diluents needed or, in some cases, withoutthe use of diluents. The hydrogels of the invention are useful in themanufacture of biomedical devices, meaning devices designed to be usedwhile in or on either or both human tissue or fluid. Examples of suchdevices include, without limitation, stents, implants, catheters, andophthalmic lenses. In a preferred embodiment, the biomedical device isan ophthalmic lens including, without limitation, contact or intraocularlenses. More preferably, the device is a contact lens.

In one embodiment, the invention provides a process for producinghydrogels comprising, consisting essentially of, and consisting of thesteps of a.) polymerizing a hydrophobic siloxane prepolymer, a silylatedhydrophilic monomer, and optionally a hydrophobic siloxane monomer toform a polymer; and b.) hydrolyzing the polymer. In another embodiment,the invention provides a hydrogel comprising, consisting essentially of,and consisting of a hydrophobic siloxane prepolymer, a silylatedhydrophilic monomer, and optionally a hydrophobic siloxane monomer.

By “hydrophobic siloxane prepolymer” and “hydrophobic siloxane monomer”is meant a siloxane prepolymer or siloxane monomer, respectively, thatdoes not have an amount of hydrophilic groups, such as a hydroxyl group,incorporated into the main chain or a side chain to allow for blends tobe made of it with a hydrophilic monomer absent the use of high levelsof diluent. Suitable hydrophobic siloxane prepolymers are of theformula:

wherein R¹ is hydrogen or an alkyl of 1 to 5 carbon atoms, R² is analkyl of 1 to 5 carbon atoms, n=1 to 12, and z=1 to 500. Preferably, theprepolymer is a macromer, such as:

wherein n and m are each independently 0 to 500 and (n+m)=10 to 500, R⁴,R⁶, R⁷, R⁸, and R⁹ are each independently a monovalent alkyl of 1 to 5carbon atoms, or aryl group that may be further substituted withalcohol, ester, amine, ketone, carboxylic acid, or ether groups, and R³,R⁵, and R¹⁰ are each independently a monovalent alkyl or 1 to 5 carbonatoms or aryl group that may be further substituted with alcohol, ester,amine, ketone, carboxylic acid or ether groups or have the structure:

providing that at least one of R³, R⁵, and R¹⁰ are according to thisstructure wherein R¹¹ is a divalent alkyl group of 1 to 5 carbon atoms,R¹² and R¹³ are independently H, a monovalent alkyl of 1 to 5 carbonatoms or aryl group that may be further substituted with an alcohol,ester, amine, ketone, carboxylic acid or ether group, or have thestructure:

wherein R¹⁶ is H or a monovalent polymerizable group containingacryloyl, methacryloyl, styryl, vinyl, allyl, or N-vinyl lactam; R¹⁸ isH, a monovalent alkyl of 1 to 5 carbon atoms or aryl group that can befurther substituted with alcohol, ester, amine, ketone, carboxylic acid,or ether groups, or a polymerizable group containing acrylate,methacrylate, styryl, vinyl, allyl or N-vinyl lactam; R¹⁴, R¹⁵, and R¹⁶are independently H, or a monovalent alkyl of 1 to 5 carbon atoms oraryl that can be further substituted with alcohol, ester, amine, ketone,carboxylic acid or ether groups, or R¹⁴ and R¹⁷, or R¹⁷ and R¹⁵ can bebonded to form a ring structure, providing that at least one of theStructure B groups on the monomer contains polymerizable groups.Preparation of such macromers is known in the art.

Preferred hydrophobic prepolymers are α,ω-bismethacryloxypropylmacromers. More preferred is α,ω-bismethacryloxypropylpolydimethylsiloxane. Other hydrophilic prepolymers that can be usedinclude linear or branched polymers or copolymers made from hydrophobicmonomers such as 3-methacryloxypropyltris (trimethylsiloxy)silane, saidprepolymers having polymerizable functional groups such as methacrylateor styryl. Preparation of such prepolymers is described in U.S. Pat.Nos. 5,010,141; 5,057,578; 5,314,960; 5,371,147 and 5,336,797incorporated in their entireties herein by reference.

In the process of the invention, the prepolymer may be used alone or incombination with a hydrophobic siloxane monomer. Hydrophobic siloxanemonomers useful in the invention are of the formula:

wherein R¹⁹ and R²⁰ are each independently hydrogen or methyl, R²¹, R²²,and R²³ are each independently a monovalent alkyl of 1 to 5 carbon atomsor aryl, j=1 to 10 and k=0 to 3. Examples of useful siloxane monomersinclude, without limitation, polysiloxyanylalkyl(meth)acrylates,preferably, 3-methacryloxypropyltris(trimethylsiloxy)silane or3-methacryloxypropylbis(trimethylsiloxy)methylsilane. Hydrophobicsiloxane monomers useful in the invention are commercially available ormay be synthesized through known methods.

In the process of the invention, the siloxane prepolymer alone, or incombination with the siloxane monomer, is polymerized with a silylatedhydrophilic monomer. Any known hydrophilic monomer capable of beingsilylated may be used. Preferably, the silylated monomer used is of theformula:

wherein R²⁴ is hydrogen or methyl, R²⁵ is hydrogen or methyl, and R²⁶ isa monoalkyl, preferably methyl. More preferably, the silylated monomeris a polyalkylsilyl ether of a hydroxyalkyl(meth)acrylamide or apolyalkylsilyl ether of a hydroxyl styrene or of a hydroxy alkylstyrene. Most preferably, the silylated monomer is2-hydroxymethacrylamide trimethylsilyl ether.

The silylated monomer may be prepared by silylating the hydroxyl groupsof a hydrophilic monomer by any known method. For example, the hydroxylgroups may be reacted with a silylating agent such as a trialkylsilylhalogenide, hexamethyldisilizane, trimethylsilyldiethylamine, or thelike. Solvents and catalysts useful in the silylation, as well asreaction conditions, are well known in the art.

The siloxane prepolymer, alone or in combination with a siloxanemonomer, are polymerized with the silylated hydrophilic monomer by anyconvenient method, including without limitation, heat, ultravioletlight, radiation polymerization, or a combination thereof. Preferably,the polymerization is carried out in the presence of a suitableinitiator present in an amount of about 0.01 to about 2.0 weight percentbased on the weight of the reactants. More preferably, thepolymerization is carried out with UV light using a UV polymerizationinitiator. The preferred UV polymerization initiator is2-hydroxy-2-methyl- 1-phenyl-propan-1-one.

The amount of siloxane prepolymer used is about 0 to about 90 weightpercent, preferably about 5 to about 70 weight percent, based on theweight of the polymerizable components. The amount of siloxane monomerused is from about 0 to about 70 weight percent, preferably from about 0to about 40 weight percent. The amount of silylated monomer used is fromabout 2 to about 60 weight percent, preferably from about 15 to about 50weight percent.

After polymerization is completed to the desired degree, the resultingpolymer may be washed in an organic solvent to remove unreactedreactants. Suitable solvents include, without limitation, hexane,ethanol, isopropyl alcohol, n- and t-butyl alcohol, n-amyl alcohol,n-hexyl alcohol, as well as chlorinated solvents and the like, andmixtures thereof.

The polymer then may be desilylated by hydrolyzing to eliminate thesilyl groups and to regenerate the hydroxyl group. The hydrolysis may becarried out in any suitable hydrolyzing agent. Preferably, hydrolysis iscarried out by placing the lenses in a borate-buffered saline solution.Optionally, an acid or base may be used in the hydrolyzing agent tospeed the hydrolysis.

One ordinarily skilled in the art will recognize that any number of awide variety of additional components may be added to the mixture to bepolymerized. Examples of such additives include, without limitation,ultra-violet absorbers, antioxidants, tints, and the like.

Any molding process may be used to form lenses from the hydrogels of theinvention. For example, the siloxane prepolymer, silylated hydrophilicmonomer and, optionally, the hydrophobic monomer may be blended togetheralong with a polymerization initiator and the blend then placed into alens mold. After polymerization is completed, the lens undergoesdesilylation.

The invention will be clarified further by a consideration of thefollowing, non-limiting examples.

EXAMPLES Example 1

214.2 g methacryloyl chloride were added dropwise to a solution of 128 gmethanol, 249 g potassium carbonate, and 122.2 g ethanolamine in athree-necked flask cooling to between 5 and 15° C. in an ice bath.Addition took approximately 3 hours after which the reaction mixture wasleft to stir for approximately 2 days after removal of the ice bath. Thereaction mixture was poured into CH₂Cl₂ and vacuum filtered to removeall solids, which solids were rinsed with CH₂Cl₂. The liquid wasinhibited with 100 ppm hydroquinone monomethyl ether and the solventremoved by rotary evaporation. Residual oil was distilled under reducedpressure in a distilling flask equipped with an air ebulator, afteraddition of 150 ppm CuCl. 56.62 g of hydroxyethyl methacrylamide wasremoved as a light yellow liquid at 0.5 mm Hg and 125 to 135° C. Air wasbubbled through the distilled product.

23 g trimethylsilyl chloride were added dropwise over an approximately 2hour period to a solution of 25.3 g of the above product, 30.6 gtriethylamine and 75 ml CH₂Cl₂ in a three-necked flask equipped with adrying tube and a magnetic stirrer. The mixture was kept at roomtemperature. After the addition, the reaction mixture was heated to 40°C. and stirred for approximately 5 hours. The mixture was then filteredto remove salt and the residual liquid was then rotovapped until theweight ceased to fall. The product was distilled under reduced pressureafter addition of 500 ppm HQMME. 2-hydroxyethylmethacrylamidetrimethylsilyl ether (“TMS-HMA”) was collected as a clear liquid at 95to 105° C. and 0.25 mm Hg in a yield of 42 percent.

Example 2

A blend was made of 20 parts of α,ω-bismethacryloxypropylpolydimethylsiloxane (5,000 average molecular wt), 45 parts of theTMS-HMA of Example 1 and 34 parts3-methacryloxypropyltris(trimethylsiloxy) silane (“TRIS”), 1 partDAROCUR™ 1173, a photoinitiator that is2-hydroxy-2-methyl-1-phenylproan-1-one, and 11 parts t-butanol. Theblend was placed in polypropylene lens molds and irradiated for 30 minwith UV light, then released in ethanol, and transferred into a boratebuffered saline to produce soft, optically clear, oxygen permeablecontact lenses.

1. A process for producing a hydrogel comprising: a.) polymerizing ahydrophobic siloxane prepoplymer and a silylated hydrophilic monomer;and b.) hydrolyzing the resulting polymer wherein the step a.)polymerizing is carried out by using one of heat polymerization,ultraviolet light polymerization, radiation polymerization, or acombination thereof.
 2. The process of claim 1 wherein the hydrophobicsiloxane prepolyer and the silylated hydrophilic monomer are polymerizedwith a hydrophobic siloxane monomer.
 3. The process of claim 2 whereinthe hydrophobic siloxane monomer is of the formula:

wherein R¹⁹ and R²⁰ are each independently hydrogen or methyl, R²¹, R²²,and R²³ are each independently a monovalent alkyl of 1 to 5 carbon atomsor aryl, j=1 to 10 and k=0 to
 3. 4. The process of claim 3, wherein thehydrophobic siloxane monomer is 3-methacryloxypropyltris(trimethylsiloxy)silane or 3-methacryloxypropylbis(trimethylsiloxy)methylsilane.
 5. The process of claim 1 or 3 whereinthe hydrophobic siloxane prepolymer is of the formula:

wherein R¹ is hydrogen or an alkyl of 1 to 5 carbon atoms, R² is analkyl of 1 to 5 carbon atoms, n=1 to 12, and z=1 to 500 and thesilylated hydrophilic monomer is of the formula:

wherein R²⁴ is hydrogen or methyl, R²⁵ is hydrogen or methyl, and R²⁶ isa monoalkyl.
 6. The process of claim 5 wherein the hydrophobic siloxaneprepolymer is a α,ω-bismethacryloxypropyl macromer and the silylatedhydrophilic monomer is a polyalkylsilyl ether of ahydroxyalkyl(meth)acrylamide.
 7. The process of claim 6 wherein thehydrophobic siloxane prepolymer is α,ω-bismethacryloxypropylpolydimethylsiloxane and the silylated hydrophilic monomer is2-hydroxymethacrylamide trimethylsilyl ether.
 8. A hydrogel comprising ahydrophobic siloxane prepolymer and a silylated hydrophilic monomer. 9.The hydrogel of claim 8 further comprising a hydrophobic siloxanemonomer.
 10. The hydrogel of claim 9 wherein the hydrophobic siloxanemonomer is of the formula:

wherein R¹⁹ and R²⁰ are each independently hydrogen or methyl, R²¹, R²²,and R²³ are each independently a monovalent alkyl of 1 to 5 carbon atomsor aryl, j=1 to 10 and k=0 to
 3. 11. The hydrogel of claim 10, whereinthe hydrophobic siloxane monomer is 3-methacryloxypropyltris(methylsiloxy)silane or 3-methacryloxypropylbis(trimethylsiloxy)methylsilane.
 12. The hydrogel of claim 8 or 10 whereinthe hydrophobic siloxane prepolymer is of the formula:

wherein R¹ is hydrogen or an alkyl of 1 to 5 carbon atoms, R² is analkyl of 1 to 5 carbon atoms, n=1 to 12, and z=1 to 500 and thesilylated hydrophilic monomer is of the formula:

wherein R²⁴ is hydrogen or methyl, R²⁵ is hydrogen or methyl, and R²⁶ isa monoalkyl.
 13. The hydrogel of claim 12 wherein the hydrophobicsiloxane prepolymer is a α,ω-bismethacryloxypropyl macromer and thesilylated hydrophilic monomer is a polyalkylsilyl ether of ahydroxyalkyl(meth)acrylamide.
 14. The hydrogel of claim 13 wherein thehydrophobic siloxane prepolymer is α,ω-bismethacryloxypropylpolydimethylsiloxane and the silylated hydrophilic monomer is2-hydroxymethacrylamide trimethylsilyl ether.
 15. The hydrogel of claim8 wherein the hydrophobic siloxane prepolymer is present in an amount ofabout 5 to about 70 weight percent and the amount of silylatedhydrophilic monomer is present in an amount of about 2 to about 60weight percent.
 16. The hydrogel of claim 9 wherein the amount ofsiloxane prepolymer used is about 5 to about 70 weight percent, theamount of siloxane monomer used is from about 0 to about 70 weightpercent, and the amount of silylated monomer used is from about 2 toabout 60 weight percent.
 17. The process of claim 1, wherein thepolymerizing step a.) is carried out using ultraviolet light.
 18. Theprocess of claim 5, wherein the polymerizing step a.) is carried outusing ultraviolet light.
 19. The process of claim 6, wherein thepolymerizing step a.) is carried out using ultraviolet light.
 20. Thehydrogel of claim 13 wherein the amount of siloxane prepolymer used isabout 5 to about 70 weight percent, the amount of siloxane monomer usedis from about 0 to about 70 weight percent, and the amount of silylatedmonomer used is from about 2 to about 60 weight percent.
 21. Thehydrogel of claim 14 wherein the amount of siloxane prepolymer used isabout 5 to about 70 weight percent, the amount of siloxane monomer usedis from about 0 to about 70 percent, and the amount of silylated monomerused is from about 2 to about 60 weight percent.